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TGM6 L517W Is Not a Pathogenic Variant for Spinocerebellar Ataxia Type 35

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TGM6 L517W Is Not a Pathogenic Variant for Spinocerebellar Ataxia Type 35 ARTICLE OPEN ACCESS TGM6 L517W is not a pathogenic variant for spinocerebellar ataxia type 35 Yanxing Chen, MD, PhD, Dengchang Wu, MD, PhD, Benyan Luo, MD, PhD, Guohua Zhao, MD, PhD, and Correspondence Kang Wang, MD, PhD Dr. Zhao [email protected] Neurol Genet 2020;6:e424. doi:10.1212/NXG.0000000000000424 or Dr. Wang [email protected] Abstract Objective To investigate the pathogenicity of the TGM6 variant for spinocerebellar ataxia 35 (SCA35), which was previously reported to be caused by pathogenic mutations in the gene TGM6. Methods Neurologic assessment and brain MRI were performed to provide detailed description of the phenotype. Whole-exome sequencing and dynamic mutation analysis were performed to identify the genotype. Results The proband, presenting with myoclonic epilepsy, cognitive decline, and ataxia, harbored both the TGM6 p.L517W variant and expanded CAG repeats in gene ATN1. Further analysis of the other living family members in this pedigree revealed that the CAG repeat number was expanded in all the patients and within normal range in all the unaffected family members. However, the TGM6 p.L517W variant was absent in 2 affected family members, but present in 3 healthy individuals. Conclusions The nonsegregation of the TGM6 variant with phenotype does not support this variant as the disease-causing gene in this pedigree, questioning the pathogenicity of TGM6 in SCA35. From the Department of Neurology (Y.C., G.Z.), the Second Affiliated Hospital, School of Medicine, Zhejiang University; and Department of Neurology (D.W., B.L., K.W.), the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. Go to Neurology.org/NG for full disclosures. Funding information is provided at the end of the article. The Article Processing Charge was funded by the authors. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 1 Glossary AD = autosomal dominant; DRPLA = dentatorubral-pallidoluysian atrophy; GTCS = generalized tonic-clonic seizure; SCA = spinocerebellar ataxia. Spinocerebellar ataxias (SCAs) are a group of autosomal members. Briefly, 22-FAM-labeled primer sets were used for dominant (AD) disorders that mainly affect the cerebellar triplet repeat primed PCR, followed by PCR product processed function. SCAs are genetically heterogeneous, and there are by capillary electrophoresis with the ABI3730xl (Applied Bio- more than 40 subtypes of SCAs and more than 30 genes systems, Foster, CA). The primer sequences of all SCAs genes identified responsible for them (neuromuscular.wustl.edu/). were designed using reference sequences from GenBank. Data SCA35 was reported to be associated with mutation in trans- were analyzed with GeneMapper v4.0 (Applied Biosystems). glutaminase 6 gene (TGM6), which codes for transglutaminase 6 protein (TG6) in 2010.1 A 4-generation Chinese AD-SCA Data availability family was identified to have 9 affected members showing The data that support the findings of this study are available progressive gait instability, scanning speech, and poor dexterity from the corresponding author on reasonable request. in hands. Linkage analysis suggested that the disease-causing gene was located on chromosome 20p13-12.2, and exome se- quencing showed that the c.1550T>G (p.L517W) variant Results cosegregated with the phenotypes. Another variant c.980A>G The proband (IV:1, figure, A) is a 28-year-old woman, who fi 2 (D327G) was identi ed in another AD-SCA family. In the presented to the neurology outpatient clinic with a 13-year ff following years, another 13 variants were reported in di erent history of unprovoked seizures. She developed generalized ethnic groups including Chinese, Asian, European, and tonic-clonic seizures (GTCSs) at age 15 years, which mainly 2–9 Hispanic, mainly in Asia. Here, we report an AD family with occurred in the morning, on awakening. She was then pre- 6 patients presenting with ataxia. Nonsegregation of the TGM6 scribed with several antiepileptic drugs, including valproate, p.L517W variant with phenotype questions the pathogenicity lamotrigine, and levetiracetam, as monotherapy or polytherapy of this variant. with different combinations, but still experiencing 3–5GTCSs each year. At age 25 years, she started to develop myoclonic jerks, which manifested with a brief, shock-like, involuntary Methods movement of the upper limbs, more severe distally and aggra- fi Participants vated by motion, and clonazepam was added with signi cant The 4-generation pedigree was recruited from the First Af- improvement. One year ago, the patient gradually exhibited filiated Hospital of Zhejiang University School of Medicine. unsteadiness, speech disturbance, and memory decline. Neu- Neurologic examination was performed by at least 2 senior rologic examination revealed mild cerebellar dysarthria, dys- fi neurologists. metria performing nger-to-nose test, and positive Romberg sign. Ophthalmoplegia, nystagmus, and saccadic movements Standard protocol approvals, registrations, were not observed. She had normal muscle strength without and patient consents rigidity, normal deep tendon reflexes, and a Mini-Mental State This study was approved by the Medical Ethics Committee of Examination score of 20. Brain MRI revealed mild atrophy of the First Affiliated Hospital of Zhejiang University School of the cerebellum and cerebral cortex (figure). Video- Medicine (No. 2017-326). Written informed consent was electroencephalography (video-EEG) showed normal back- obtained from each participant or from a legal representative. ground activities and intermittent spikes involving the posterior head region. Photic sensitivity was absent. Considering the Genetic analysis progressiveness and the involvement of multiple neurologic Genomic DNA was extracted from the peripheral blood of systems of this patient, inherited neurodegenerative diseases family members. Exon-enriched DNA sequencing and bio- were suspected. Whole-exome sequencing identified a reported informatic analysis were performed on the Illumina HiSeq variant c.1550T>G (p.L517W) in the TGM6 gene. Given that X-ten (Illumina, CA) in high-output mode with 150 bp paired- epilepsy has not been reported in patients with TGM6 muta- end reads following the manufacturer’s instructions (Illumina) tions, we further studied ataxia caused by trinucleotide (or in the proband. The suspected pathogenic variants were vali- pentanucleotide) repeat expansion. Surprisingly, genetic testing dated by Sanger sequencing. The results of Sanger sequencing using capillary electrophoresis revealed 14/61 CAG repeats in performed in other living family members were used for the atrophin-1 (ATN1) gene on chromosome 12p13.31, which cosegregation analysis. A dedicated panel for screening SCAs is a well-established gene for DRPLA. However, this raises the including SCA1, 2, 3, 6, 7, 8, 10, 12, 17, and dentatorubral- question whether this patient happened to harbor double pallidoluysian atrophy (DRPLA) was used to test repeat mutations, which might have additive effects on the phenotype, expansions of related mutations in all the available family or the TGM6 p.L517W variant is not actually pathogenic. 2 Neurology: Genetics | Volume 6, Number 3 | June 2020 Neurology.org/NG Figure Family pedigree and brain MRI of the proband (A) Family pedigree of DRPLA disease. (B) Brain MRI of the proband showing mild cerebellar atrophy. (C) Normal control of the TGM6 gene. (D) The TGM6 variant in the patient. Arrows indicate the variant site. DRPLA = dentatorubral-pallidoluysian atrophy. We subsequently studied the whole family and found that unstable CAG trinucleotide repeat expansion in ATN1. Nor- family members I:2, II:1, II:3, III:1, and III:5 developed cere- mally, the CAG tract bears 6–35 repeats, which expands to over bellar ataxia and cognitive decline/dementia in their fifties or 49 in patients with DRPLA.10 The clinical features of DRPLA sixties (table). The TGM6 p.L517W variant was absent in are strikingly heterogeneous, depending on the age at disease patients III:5 and II:3, but present in unaffected individuals (II: onset and the prominent genetic anticipation.11 Patients with 4, III:3, and III:7). The nonsegregation of the TGM6 variant juvenile-onset (onset before age 20 years) frequently exhibit with phenotype does not support this variant as the disease- progressive myoclonic epilepsy, intellectual disabilities, and causing gene in this family. On the other hand, the CAG repeat ataxia. Various forms of seizures are common features in all number was expanded in all the patients (II:3, III:1, III:5, and patients with onset before age 20 years. Patients with onset IV:1) and within normal range in all the unaffected family after age 20 years typically present symptoms including cere- members with available DNA, perfectly cosegregating with bellar ataxia, choreoathetosis, and dementia. Therefore, the disease phenotype. No DNA was available from the deceased clinical manifestations of the proband comply with juvenile- patients (I:1, I:2, and II:1). Patient II:1 died of gastric cancer at onset DRPLA, while the other affected family members also fit age 53 years. The presence of the ATN1 variant in her children well
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